tbuckley/cabot-search huggingface dataset:
Performance measures for the SACRED team-centered approach to advanced gastrointestinal endoscopy: European Society of Gastrointestinal Endoscopy (ESGE) Quality Improvement Initiative
Authors: Hey-Long Ching, Michelle S. Lau, Iman A. Azmy, Andrew D. Hopper, Martin Keuchel, Tibor Gyökeres, Roman Kuvaev, Elisabeth J. Macken, Pradeep Bhandari, Mo Thoufeeq, Philippe Leclercq, Matthew D. Rutter, Andrew M. Veitch, Raf Bisschops, David S. Sanders
Journal: Endoscopy (2022)

Abstract The European Society of Gastrointestinal Endoscopy and United European Gastroenterology have defined performance measures for upper and lower gastrointestinal, pancreaticobiliary, and small-bowel endoscopy. Quality indicators to guide endoscopists in the growing field of advanced endoscopy are also underway. We propose that equal attention is given to developing the entire advanced endoscopy team and not the individual endoscopist alone. We suggest that the practice of teams intending to deliver high quality advanced endoscopy is underpinned by six crucial principles concerning: selection, acceptance, complications, reconnaissance, envelopment, and documentation (SACRED).
DIPG-27. Behavioral disturbances as underestimated presenting symptoms in children with Diffuse Intrinsic Pontine Glioma (DIPG)
Authors: Claudia Milanaccio, Sonia Di Profio, Sara De Giuseppe, Antonia Ramaglia, Antonio Verrico, Marco Crocco, Gianluca Piccolo, Camilla Satragno, Veronica Biassoni, Maria Luisa Garrè
Journal: Neuro-Oncology (2022)

Abstract PURPOSE: to describe how often behavioral and emotional changes occur at diagnosis in children with DIPG, or precede it. METHODS: the anamnesis, clinical history, psychological evaluation, and onset symptoms of all cases of DIPG diagnosed at Gaslini Institute between January 2010 and December 2020 were reviewed. RESULTS: 20 DIPGs were diagnosed, 7 males, with a median age of 7,6 years (range 2,4-16,2). All patients presented typical neurological symptoms: 16 had cranial nerves palsy, 12 ataxia, 8 dysarthria, 5 dysphagia, 5 hemiparesis, 5 headache, and 2 obstructive hydrocephalus. Behavioral disorders were found in 14 cases, with several manifestations and in various association: irritability and aggressive behavior in 6, ideomotor slowdown and apathy in 5, emotional dysregulation in 4, mood deflection in 3, sleep disturbances (i.e. nightmares, insomnia, and somniloquy) in 3, marked behavioral changes, school phobia and separation anxiety in 2, depersonalization crisis and phobia of waterdrops in the eyes in 2 patients each. In 6 cases behavioral disturbances were the presenting symptom, appearing one to twelve months earlier than the classic neurological deficits. In all patients, behavioral symptoms improved during Radiotherapy. CONCLUSIONS: behavioral disturbances, although well-known and described in the literature, are not commonly reported among the onset symptoms of DIPG, thus being probably underestimated. Their pathogenesis can be explained by neurophysiology: the brainstem contains reciprocal cerebro-ponto-cerebellar connections whose disruption compromises their modulatory function on affective and cognitive behavior. Furthermore, the reticular formation contains aggregates of neurons regulating several complex functions including the state of alertness (e.g. sleep and wakefulness), the perception of pain, and cognitive functions (e.g. attention, mood, and memory). A careful anamnestic and medical history together with a detailed psychological assessment should be always performed in all DIPGs at diagnosis, in order to bring out those underlying behavioral disorders which could benefit from early neuropsycological support.
Ursolic acid reduces inflammation and fibrosis in the kidney of diabetic mice
Authors: SA Manea, AG Lazar, ML Vlad, A Manea
Journal: Cardiovascular Research (2022)

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): UEFISCDI Background Diabetic kidney disease (DKD) is arguably the major disabling and life-threatening microvascular-related disorder associated with both type I and type II diabetes. Inflammation of glomerular capillary system and progressive accumulation of glomerular extracellular proteins are important culprit mechanisms leading to glomerulosclerosis and ultimately renal failure in end-stage DKD. Conventional anti-diabetic therapies can only delay the progression of DKD. The naturally-occurring triterpenic acids emerged as important candidate pharmacological compounds for the treatment of cardiometabolic disorders. Purpose We aimed at investigating the potential regulatory effects of ursolic acid, a pentacyclic triterpenoid, on the expression of key pro-inflammatory and pro-fibrotic mediators in diabetic kidney. Methods Non-diabetic and streptozotocin-induced diabetic C57BL/6J male mice were randomized to receive via intraperitoneal injection 1 mg/kg ursolic acid (UA), or its vehicle (5% DMSO + 95% PBS, pH 7.4), for 4 weeks. Human endothelial cells (EC) were exposed to normal (5 mM) or high (25mM) concentration of glucose in the absence/presence of 1-10 μM UA. Real-time PCR, Western blot, and immunofluorescence microscopy techniques were employed to investigate the expression of selected DKD-relevant pro-inflammatory and pro-fibrotic molecules. Morphological aspects of the kidney and glomeruli were assessed by histochemistry. Results The mRNA/protein levels of pro-inflammatory (MCP-1, TNFα, NOS2, ICAM-1, VCAM-1, E-selectin) and pro-fibrotic (collagen IV, fibronectin, laminin, TGFβ) mediators were found significantly elevated in the kidney of diabetic mice as compared to non-diabetic counterparts. Treatment of diabetic mice with UA significantly reduced the up-regulated expression of pro-inflammatory mediators, extracellular matrix proteins, and pro-fibrotic factor TGFβ. Moreover, glomerular hypertrophy and the up-regulation of glomerular collagen IV, fibronectin, and laminin protein levels were significantly reduced in UA-treated diabetic mice. In cultured human EC, UA suppressed the high glucose-induced up-regulation of ICAM-1, VCAM-1, E-selectin and NF-kB signaling. Conclusion In experimental diabetes, ursolic acid down-regulates the expression of DKD-relevant pro-inflammatory and pro-fibrotic molecules in the kidney of diabetic mice by potentially targeting NF-kB signaling pathway. The data of this study suggest that triterpenic acids and their chemical derivates could become important pharmacological tools to reduce inflammation and fibrosis associated with DKD.
Prognostic significance of the CP-GEP assay combining clinicopathologic factors and gene expression profiling in patients (pts) with AJCC v8 stage I/II cutaneous melanoma (CM).
Authors: Teresa Maria Santos Amaral, Tobias Sinnberg, Eftychia Chatziioannou, Heike Niessner, Ulrike M. Leiter, Ulrike Keim, Andrea Forschner, Jvalini Dwarkasing, Lisette Meerstein-Kessel, Thomas Rademaker, Renske Wever, Alexander M. Eggermont, Lukas Flatz, Stephan Forchhammer
Journal: Journal of Clinical Oncology (2022)

9564 Background: AJCC v8 includes Breslow thickness and ulceration to subdivide stage I and II CM pts into risk groups. In light of the results from adjuvant therapy in stage II CM, it has been discussed that pts’ follow-up and eventually treatment should consider additional markers, namely CP-GEP, to further refine the risk classification provided by the AJCC v8. The aim of this single center study was to clinically validate a prognostic CP-GEP-based risk score for stage I/II CMs combining Breslow, age and the expression of 8 genes SERPINE2, GDF15, ITGB3, CXCL8, LOXL4, TGFBR1, PLAT and MLANA. Methods: All obtainable formalin-fixed paraffin-embedded primaries of stage I/II CMs with negative sentinel lymph node (SLN) from the Central Malignant Melanoma Registry of Germany diagnosed between 2000-2017 and archived in Tuebingen were included. Study hypothesis and protocol were prospectively formulated. Tumors were analyzed blinded to clinical outcome. Quantitative reverse transcription polymerase chain reaction of the 8 genes was performed and combined with age and tumor thickness to define CP-GEP low- vs. high-score groups. Relapse-free survival (RFS), distant metastasis free survival (DMFS) and overall survival (OS) were evaluated using Kaplan-Meier curves. CP-GEP score performance was tested using multivariate Cox regression adjusted for tumor thickness, ulceration and age. Results: We included 543 pts with Stage IA (n=78); IB (n=223); IIA (n= 123); IIB (n=73); IIC (n=46). 43% were females, median Breslow was 1.7mm and 25% of tumors had ulceration. The median follow-up was 78 months (IQR 47-116). 311 (57%) patients had a high-risk CP-GEP score. The 5-y RFS rate was 71% and 92% (HR 4.2; p&lt;0.001), the 5-y DMFS rate was 86% and 96% (HR 4.35; p&lt;0.001) and the 5-y OS was 85% and 95% (HR 3.2; p=0.001), respectively for high and low-risk CP-GEP score. In multivariate Cox regression analysis for RFS including Breslow thickness, ulceration and age, contribution of CP-GEP score remained independently significant (HR 2.75; p=0.0008) compared to age (HR 1.03; p&lt;0.0007), Breslow (HR 1.21; p&lt;0.0001) and ulceration (HR 1.37; p=0.1694). Conclusions: CP-GEP risk score is a non-invasive and independent prognostic model for risk of relapse in stage I/II melanoma validated in this study. It identifies SLN negative pts at high risk of relapse and should be considered for complementing AJCC classification and for inclusion in future clinical trials.[Table: see text]
Solitary Fibrous Tumor of the Bone Detected by FDG PET/CT
Authors: Jie Li, Anren Kuang, Guohua Shen
Journal: Clinical Nuclear Medicine (2022)

Abstract Solitary fibrous tumor as a rare mesenchymal tumor can occur in a wide variety of body sites, including serosal membranes, liver, lung, and deep soft tissues; however, primary tumor arising in bone is rarely documented. Herein, we reported the MRI, bone scan, and FDG PET/CT findings of a primary spinal solitary fibrous tumor in a 39-year-old woman.
Pathways and perceived barriers to paediatric urology subspecialisation: A study of incumbent attitudes and opinions
Authors: F. O'Kelly, L. T' Hoen, B. Banuelos, R. Lammers, A. Radford, S. Sforza, M. Hiess, E. Bindi, A-F. Spinoit, M.S. Silay, B. Haid
Journal: European Urology (2022)
Temporal evolution in quality of life following melphalan percutaneous hepatic perfusion for patients with metastatic uveal melanoma.
Authors: Ganesh Vigneswaran, Pippa Woodcock, Tom Gibson, Shian Patel, Maryam Adil, Matthew Wheater, Ioannis Karydis, Sanjay Gupta, Brian Stedman, Sachin Modi
Journal: Journal of Clinical Oncology (2022)

e21520 Background: Recent studies have demonstrated a clear survival benefit of melphalan percutaneous hepatic perfusion (M-PHP) for liver metastases from ocular melanoma (mUM). Importantly, the survival benefit relating to each treatment cycle must be carefully balanced with changes in patient Quality of Life. We contribute our single centre findings on the temporal change in the quality of life after M-PHP therapy. Methods: We performed a retrospective analysis of the change in quality of life (QoL) using the Functional Assessment of Cancer Therapy - General (FACT-G) with mUM patients receiving M‐PHP at our institutions (n = 13). The FACT-G score which comprises physical (PWB), social (SWB), emotional (EWB) and functional (FWB) wellbeing were measured pre-procedure and at day 1, day of discharge, 7, 14 and 28 days after M-PHP therapy. Paired t-test was used to assess for any significant change in each QoL domain. Results: The baseline FACT-G score was 93.4 out of 108 +/- 14.7 (mean +/- std). Quality of life scoring significantly decreased immediately after the procedure (day 1; 84.8 +/- 13.1, p = 0.01) and gradually improved over time, with no significant difference in total score by the day of discharge; 88.7 +/- 13.7, c.f baseline p = 0.22). By day 28, there was a trend for overall improved QoL (96.6 +/-9.3, p = 0.25). Sub-score analysis revealed that by day 28 there was a statistically significant improvement in EWB (p = 0.02), a trend towards improved scores in PWB and SWB domains. FWB was slightly below baseline by day 28 (23.8 vs 23.2). Conclusions: Quality of life following M-PHP decreases immediately after therapy and is not significantly different from baseline by the day of discharge. By day 28 there is a trend towards improved overall quality of life. This study could provide the basis for determining the optimal time between treatment cycles.
Artificial intelligence in gastroenterology and hepatology: how to advance clinical practice while ensuring health equity
Authors: Eugenia Uche-Anya, Adjoa Anyane-Yeboa, Tyler M Berzin, Marzyeh Ghassemi, Folasade P May
Journal: Gut (2022)

Artificial intelligence (AI) and machine learning (ML) systems are increasingly used in medicine to improve clinical decision-making and healthcare delivery. In gastroenterology and hepatology, studies have explored a myriad of opportunities for AI/ML applications which are already making the transition to bedside. Despite these advances, there is a risk that biases and health inequities can be introduced or exacerbated by these technologies. If unrecognised, these technologies could generate or worsen systematic racial, ethnic and sex disparities when deployed on a large scale. There are several mechanisms through which AI/ML could contribute to health inequities in gastroenterology and hepatology, including diagnosis of oesophageal cancer, management of inflammatory bowel disease (IBD), liver transplantation, colorectal cancer screening and many others. This review adapts a framework for ethical AI/ML development and application to gastroenterology and hepatology such that clinical practice is advanced while minimising bias and optimising health equity.
Impact of acetaminophen on the efficacy of immunotherapy in cancer patients
Authors: A. Bessede, A. Marabelle, J.P. Guégan, F.X. Danlos, S. Cousin, F. Peyraud, N. Chaput, M. Spalato, G. Roubaud, M. Cabart, M. Khettab, A. Chaibi, C. Rey, I. Nafia, F.X. Mahon, J.C. Soria, A. Italiano
Journal: Annals of Oncology (2022)
Evaluation of the bone-testis axis in patients with azoospermia undergoing surgical sperm retrieval
Authors: J. Kilb-Köklü, A. Pilatz, K.S. Lips, D. Fietz, T. El Khassawna, G.A. Krombach, T. Diemer, H-C. Schuppe, R. Stange, C. Heiss, F. Wagenlehner
Journal: European Urology (2022)
Prognostic value of <i>EZH2</i> expression for immunotherapy-based schemes in advanced soft-tissue sarcoma: A translational research from Spanish Group of Research on Sarcoma (GEIS).
Authors: David Silva Moura, Jorge Zamora, Nadia Hindi, Maria Lopez-Alvarez, Serena Lacerenza, Giovanni Grignani, Javier Martinez-Trufero, Andres Redondo, Claudia Maria Valverde Morales, Silvia Stacchiotti, Antonio Lopez-Pousa, Antonio Gutierrez, Jose A. Lopez-Martin, Javier Martin Broto
Journal: Journal of Clinical Oncology (2022)

11549 Background: Immunotherapy-based treatments had shown to be active in several solid tumors, including in selected subtypes of sarcomas. IMMUNOSARC (NCT03277924) is a phase Ib/II trial [from Spanish (GEIS) and Italian (ISG) sarcoma groups], that tested the combination of nivolumab (anti-PD-1 inhibitor) plus sunitinib (anti-angiogenic agent) in advanced sarcomas. Among the 65 soft-tissue sarcoma (STS) patients (pts) enrolled, 48% were free of progression at 6 months, meeting the trial’s primary endpoint. EZH2 is the catalytic subunit of the Polycomb Repressive Complex 2 and it has been described to play an important role in the transcriptional repression of genes involved in T-cell migration and T-cell-mediated anti-tumor activity. The aim of this study was to explore the value of EZH2 gene expression as potential prognostic biomarker of the activity of immunotherapy-based schemes. Methods: The expression of EZH2 was evaluated in 64 paraffin tumor blocks, by direct transcriptomics, using HTG EdgeSeq Oncology Biomarkers Panel (HTG Molecular Diagnostics, Inc.; Tucson, AZ, USA). Data was normalized with DESeq2 and the cut-off of EZH2 expression was calculated with MAXSTAT R package. Gene expression was correlated with progression-free survival (PFS) by RECIST, overall survival (OS) and clinical benefit (patients with response or stable disease vs patients with progressive disease as best response). Results: Among the 64 pts analyzed, 52 (81%) showed overexpression of EZH2, considering a cut-off of 570.15 read counts. Undifferentiated pleomorphic sarcoma (UPS) and epithelioid sarcoma were the subtypes with higher expression of EZH2 with a median of read counts of 1888.04 (n = 10) and 1261.79 (n = 7), respectively. The lowest expressions were observed in extraskeletal myxoid chondrosarcoma (ECM) and alveolar soft-part sarcoma (ASPS) with a median of read counts of 461.42 (n = 4) and 680.84 (n = 7), respectively. Low expression of EZH2 was associated with better PFS (16.8 months vs. 3.9 months; p = 0.001) and better OS (NR vs. 20.0 months; p = 0.006). Moreover, low expression of EZH2 was also significantly associated with a clinical benefit of the patients treated with nivolumab plus sunitinib [relative risk (RR): 13; 95% CI: 3.0-56.9; p = &lt; 0.001). Conclusions: Low expression of EZH2 was associated with better outcome in advanced STS patients treated with immunotherapy-based schemes. These results might support the rationale for the combination of EZH2 inhibitors with immune-modulating agents for future studies.
MicroRNA-124-3p-enriched small extracellular vesicles as a therapeutic approach for Parkinson’s disease
Authors: Marta Esteves, Ricardo Abreu, Hugo Fernandes, Catarina Serra-Almeida, Patrícia A.T. Martins, Marta Barão, Ana Clara Cristóvão, Cláudia Saraiva, Raquel Ferreira, Lino Ferreira, Liliana Bernardino
Journal: Molecular Therapy (2022)

Parkinson's disease is a neurodegenerative disease characterized by the loss of dopaminergic neurons in the substantia nigra with no effective cure available. MicroRNA-124 has been regarded as a promising therapeutic entity for Parkinson's disease due to its pro-neurogenic and neuroprotective roles. However, its efficient delivery to the brain remains challenging. Here, we used umbilical cord blood mononuclear cell-derived extracellular vesicles as a biological vehicle to deliver microRNA (miR)-124-3p and evaluate its therapeutic effects in a mouse model of Parkinson's disease. In vitro, miR-124-3p-loaded small extracellular vesicles induced neuronal differentiation in subventricular zone neural stem cell cultures and protected N27 dopaminergic cells against 6-hydroxydopamine-induced toxicity. In vivo, intracerebroventricularly administered small extracellular vesicles were detected in the subventricular zone lining the lateral ventricles and in the striatum and substantia nigra, the brain regions most affected by the disease. Most importantly, although miR-124-3p-loaded small extracellular vesicles did not increase the number of new neurons in the 6-hydroxydopamine-lesioned striatum, the formulation protected dopaminergic neurons in the substantia nigra and striatal fibers, which fully counteracted motor behavior symptoms. Our findings reveal a novel promising therapeutic application of small extracellular vesicles as delivery agents for miR-124-3p in the context of Parkinson's disease.
Can Drug Repurposing Accelerate Precision Oncology?
Authors: Luuk J. Schipper, Laurien J. Zeverijn, Mathew J. Garnett, Emile E. Voest
Journal: Cancer Discovery (2022)

Abstract Ongoing new insights in the field of cancer diagnostics, genomic profiling, and cancer behavior have raised the demand for novel, personalized cancer treatments. As the development of new cancer drugs is a challenging, costly, and time-consuming endeavor, drug repurposing is regarded as an attractive alternative to potentially accelerate this. In this review, we describe strategies for drug repurposing of anticancer agents, translation of preclinical findings in novel trial designs, and associated challenges. Furthermore, we provide suggestions to further utilize the potential of drug repurposing within precision oncology, with a focus on combinatorial approaches. Significance: Oncologic drug development is a timely and costly endeavor, with only few compounds progressing to meaningful therapy options. Although repurposing of existing agents for novel, oncologic indications provides an opportunity to accelerate this process, it is not without challenges.
Phase 1b/2 study of GX-I7 plus pembrolizumab in patients with refractory or recurrent (R/R) metastatic triple-negative breast cancer (mTNBC): The KEYNOTE-899 Study.
Authors: Joohyuk Sohn, Gun Min Kim, Keun Seok Lee, Sung-Bae Kim, Jee Hung Kim, Hee Kyung Ahn, JIEUN LEE, Kyong Hwa Park, Jee Hyun Kim, Kyoung Eun Lee, Eui-Cheol Shin, Su-Hyung Park, Se Hwan Yang, MinKyu Heo, Jung Won Woo, Young Chul Sung, Young Hyuck Im
Journal: Journal of Clinical Oncology (2022)

1081 Background: GX-I7 (efineptakin alfa) is a hybrid Fc-fused long-acting recombinant human IL-7 which plays an essential role in the development and homeostasis of T-cells. GX-I7 can potentially enhance the anti-tumor effect of pembrolizumab via induction of T-cell activity. Here, we report results of phase 1b/2 study of GX-I7 plus pembrolizumab in patients with R/R mTNBC. Methods: Eligible patients had R/R mTNBC that failed up to 3 rd lines of chemotherapy in the metastatic setting. Phase 1b patients received GX-I7 in 5 dose levels ranging from 360 µg/kg to 1,440 µg/kg every 9 (Q9W) or 12 (Q12W) weeks plus pembrolizumab 200 mg Q3W (n=51). Phase 2 is an expansion cohort where 33 patients were treated with the recommended phase 2 dose (RP2D). The primary objective was to determine the RP2D for phase 1b and to assess the objective response rate (ORR) for phase 2. Results: The study included 84 patients (phase 1b, n=51; phase 2, n=33) and 53.6% (45/84) of patients have received 2 nd to 3 rd lines of previous therapy. In phase 1b, one dose-limiting toxicity (DLT; grade 3 skin rash) was reported in the 1,440 µg/kg cohort and GX-I7 1,200 µg/kg Q9W was selected as RP2D. The ORRs were 15.7% [95% confidence interval (CI): 7.0 – 28.6] for phase 1b (n=51) and 21.2% [95% CI: 9.0 – 38.9] for phase 2 (n=33). Median PFS was 2.4 months (95% CI: 2.1 – 2.7) at the median follow-up of 10.4 months for all patients combined (n=84). GX-I7 induced up to 3.6-fold (range 1.2 – 8.1) increase in absolute lymphocyte counts (including CD4+ and CD8+ T cell) in all dose levels. The most common treatment-related adverse events (AEs) of any grade were injection site reaction (50.0%), ALT increased (39.3%), pyrexia (38.1%) and rash (35.7%). The additional correlative study data will be presented. Conclusions: GX-I7 in combination with pembrolizumab demonstrated a manageable safety profile with promising anti-tumor activity in patients with R/R metastatic TNBC. Clinical trial information: NCT03752723. [Table: see text]